The response of intrinsic brain cells to virus infection in the central nervous system (CNS) can contribute both to the pathogenesis of the virus infection as well as to the protection of the host. Our studies have utilized a mouse model of polytropic retrovirus infection to examine both the pathogenic and protective responses of the host in the CNS during virus infection. One of the strongest correlates of polytropic retrovirus neurovirulence is production of high levels of proinflammatory cytokines and chemokines and the activation of microglia and astrocytes. We have utilized mice deficient in different host response genes to identify the host genes that play an important role in regulating (1) virus replication in the CNS, (2) virus-induced innate immune responses and (3) neuropathogenesis. We have generated chimeric viruses that differ in neurovirulence to correlate host responses to those viruses and neurovirulence. In FY09, we primarily focused on one polytropic retrovirus that replicates to a high level in the CNS and induces a pronounced innate immune response in the CNS, including the upregulation of several proinflammatory cytokines. However, studies with knockout mice demonstrated that many of these proinflammatory responses did not play a role in pathogenesis. Further studies using real-time PCR arrays, mutant viruses and knockout mice identified a protein produced by neurons that appears to play a protective role during retrovirus infection and limit disease induction. Our current studies are directed at understanding the role of this protein in viral pathogenesis.